The concept of a coupled communication between osteoblastic bone formation and osteoclastic bone resorption was first described in humans by Harris and Heaney in 1969 (Harris W H. Heaney R. P., New England Journal of Medicine. 280(5):253-9 contd, 1969; Harris W H. Heaney R P., New England Journal of Medicine. 280(6):303-11 concd 1969). They showed that in patients with high rates of resorption there was a correspondingly high rate of bone formation and concluded that the maintenance of a steady state skeletal mass required that osteoclastic bone resorption be matched in amount by osteoblastic bone formation. They based their investigations on conceptual principles put forward by Frost (Epker B N. Frost H M., Henry Ford Hospital Medical Journal. 16(1):29-39, 1968; Villanueva A R. et al., Clinical Orthopaedics & Related Research. 49:135-50, 1966; Frost H M., Journal of Bone & Joint Surgery—American Volume. 48(6):1192-203, 1966) and Parfit (Parfitt A M., Clinical Obstetrics & Gynecology. 30(4):789-811, 1987; Parfitt A M., Metabolism: Clinical & Experimental. 25(8):909-55, 1976). William Harris and Robert Heaney coined the term “coupling.”
Coupling was defined at a molecular and cellular level by Howard, Baylink and others (Howard G A. et al., Progress in Clinical & Biological Research. 101:259-74, 1982; Howard G A. et al., Proceedings of the National Academy of Sciences of the United States of America. 78(5):3204-8, 1981; Baylink D. et al., Advances in Experimental Medicine & (Biology. 151:409-21, 1982.) as a release of growth factors from bone during resorption leading to the subsequent activation and differentiation of osteoblasts for the process of bone formation. They presented evidence for a “coupling factor” that could be recovered in the medium of bone undergoing resorption. Coupling factor turned out to be a number of molecules including the IGF's, TGFβ's and BMP's.
Therefore, both systemic hormones such as PTH and local factors such as the TGFβ's, BMP's and IGF's are molecules with the potential to stimulate both osteoblast number and osteoblast differentiation. However, what has not been universally appreciated as part of the remodeling process is that bone formation occurs on the immediate surface of the resorptive event. That is, growth factor diffusion from a resorption site occurs with a larger radius than is encompassed by the actual site of bone formation, yet bone is deposited at the site of bone resorption. This argues that there must be a site-specific localization to the formation process. Teleologically, this makes sense, since if bone were deposited at sites other than those undergoing resorption, it might lead to alteration of trabecular architecture and contribute to the formation of structurally unsound bone.
Osteoclastic bone resorption depends on the formation of adhesive bonds between the cell and the bone surface as well as the formation of two critical ultrastructural features; the ruffled boarder and sealing (or clear) zone. At the ruffled border the cell actively pumps large numbers of protons into the space between the cell and bone. pH is decreased to the range of approximately 5.0 to 6.0 and the hydroxyapatite becomes soluble. Secretion of lysosomal enzymes and other acidic hydrolases into this space begins the process of collagen and non-collagen protein breakdown. In many ways the space between the osteoclast and the bone surface becomes an extracellular lysosome characterized by high levels of lysosomal enzymes and a low pH. In fact, the brush border membrane of the osteoclast has been shown to contain high levels of the mannose-6-phosphate receptor (A1 Kawas S. et al., Calcified Tissue International. 59(3):192-9, 1996; Blair H C. et al., Clinical Orthopaedics & Related Research. (294):7-22, 1993 September; Baron R. et al., Journal of Cell Science. 97 (Pt 3):439-47, 1990; Baron R. et al., Journal of Cell Biology. 106(6):1863-72, 1988 June). This receptor is responsible for trafficking lysosomal enzymes to a lysosome. When present on osteoclast (or ameloblast) brush border membranes it presumably can direct these enzymes to the active resorbing surface. These osteoclast enzymes remain firmly attached to the resorption surface (Xia L. et al., Biological Chemistry. 380(6):679-87, 1999 June; Romano P R. et al., Journal of Periodontal Research. 32(1 Pt 2):143-7, 1997).
Mannose-6-phosphate moieties present on lysosomal enzymes have the ability to activate the mannose-6-phosphate receptor. Since the mannose-6-phosphate receptor shares identity with the IGF-II receptor, activation of this receptor by lysosomal enzymes could induce a growth factor like effect (Ishibe, M., et al., J. Clin. Endocrinol. Metab. 73: 785-792 (1991); Ishibe, M., et al., Endocrine Research. 17: 357-366 (1991); Martinez, D. A., et al., (1995) J. Cellular Biochemistry 59: 246-257; Ishibe, M., et al., Cal. Tissue Intl. 63:36-38 (1998).).
Thus, there exists a need for identification of the molecules involved in mediating the osteoblast/osteoclast/osteoclast lacuna interactions and signalings. Disclosed herein are compositions and methods that are involved in these interactions and can mediate the bone resorptive/formative event.